Low birth weight, uterine infection, and nitric oxide

低出生体重、子宫感染和一氧化氮

• 批准号: 7064798
• 负责人: CHANDRASEKHAR YALLAMPALLI
• 金额: $ 32.74万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-30 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064798
• 关键词: Escherichia coli; Escherichia coli infections; Streptococcus agalactiae; Streptococcus infection; bacteria infection mechanism; bacterial cytopathogenic effect; decay accelerating factor; host organism interaction; human birth weight; human morbidity; human mortality; immunocytochemistry; laboratory rat; nitric oxide; nitric oxide synthase; nucleic acid purification; placenta; polymerase chain reaction; pregnancy infection; prenatal growth disorder; uterus; western blottings; women' s health

DESCRIPTION (provided by applicant): Urogenital infections and host factors are often associated with low birth weight, especially in minority populations. Most pathogens, including Escherichia coli, develop unique virulence mechanisms to colonize and invade the urogenital tract. Bacterial adhesins such as Dr fimbriae of E col interact with host tissue receptors allowing ascending infection and associated complications. Nitric oxide (NO), a gaseous molecule with versatile functions including the modulation of infection and immunity, is reported to be produced by uteroplacental tissues. The goal of this project is to assess if NO modulates severity of uterine infection through the regulation of bacterial invasion into cells. We hypothesize that the NO system regulates the uteroplacental bacterial receptor, decay accelerating factor (DAF), and therefore bacterial invasion. We propose that this novel mechanism could play a role in severity of infection and perinatal morbidities such as low birth weight. These hypotheses will be tested by pursuing three specific aims. Specific Aim 1 will determine whether NO inhibits Dr+ E coil attachment and internalization into epithelial cells and whether this occurs through suppression of DAF expression. Sub-aim 1.1 will characterize NO production, NO synthase (NOS) enzymes in uterine epithelial cell lines, Ishikawa, RL-95 and HEC-1 cells. Sub-aim 1.2 will test the hypothesis if manipulation of NO synthesis in these cells will alter Dr +E coil attachment and internalization. Sub-aim 1.3 will test the hypothesis that the epithelial cell DAF protein and mRNA contents are regulated by NO system. Specific Aim 2 will establish that modulation of NO synthesis in rats will alter severity of infection through the changes in DAF content of the uterus and vasculature in experimental intrauterine infection. Sub-aim 2.1 will test the hypothesis that Dr* E coil or group B streptococcus (GBS) infection in uteroplacental tissues is reduced with increases in NO synthesis and is increased with the inhibition of NO synthesis. Sub-aim 2.2 will test the hypothesis that changes in DAF content of uteroplacental and vascular tissues are related to changes in NO synthesis. Specific Aim 3 will examine if inhibition of NO synthesis and experimental intrauterine Dr E coil or GBS infection results in fetal growth restriction in rats, and if so, whether NO donor can reverse the fetal growth restriction. Sub-aim 3.1 will test the hypothesis that inhibition of NO synthesis combined with intrauterine Dr+E coil or GBS infection has synergistic detrimental effects on fetal and placental growth. Sub aim 3.2 will test the hypothesis that NO donor can reverse the increases in DAF expression in uteroplacental and vascular tissues and in fetal growth restriction.

描述（由申请人提供）：泌尿生殖道感染和宿主因素通常与低出生体重相关，特别是在少数民族人群中。大多数病原体，包括大肠杆菌，发展独特的毒力机制，殖民和侵入泌尿生殖道。细菌粘附素，如大肠杆菌菌毛与宿主组织受体相互作用，使上行感染和相关并发症。一氧化氮（NO）是一种气体分子，具有多种功能，包括感染和免疫调节，据报道，由子宫胎盘组织产生。该项目的目标是评估NO是否通过调节细菌侵入细胞来调节子宫感染的严重程度。我们假设NO系统调节子宫胎盘细菌受体、衰变加速因子（decay accelerating factor，ERF），从而调节细菌入侵。我们认为这种新的机制可能在感染的严重程度和围产期发病率（如低出生体重）中发挥作用。这些假设将通过追求三个具体目标来检验。特异性目的1将确定NO是否抑制Dr+ E螺旋附着和内化到上皮细胞中，以及这是否通过抑制DR表达而发生。子目标1.1将表征子宫上皮细胞系、石川、RL-95和HEC-1细胞中的NO产生、NO合酶（NOS）酶。子目标1.2将检验在这些细胞中操纵NO合成是否会改变Dr +E螺旋附着和内化的假设。子目标1.3将验证上皮细胞中NO系统调节其蛋白和mRNA含量的假设。具体目标2将确定大鼠中NO合成的调节将通过实验性宫内感染中子宫和脉管系统的脂质含量的变化来改变感染的严重程度。子目标2.1将检验以下假设：子宫胎盘组织中Dr* E coil或B组链球菌（GBS）感染随着NO合成的增加而减少，随着NO合成的抑制而增加。子目标2.2将检验子宫胎盘和血管组织中NO含量的变化与NO合成的变化相关的假设。具体目标3将检查NO合成的抑制和实验性宫内Dr E coil或GBS感染是否导致大鼠的胎儿生长受限，如果是，NO供体是否可以逆转胎儿生长受限。子目标3.1将检验抑制NO合成与宫内Dr+E coil或GBS感染联合对胎儿和胎盘生长具有协同有害作用的假设。子目标3.2将检验一氧化氮供体可以逆转子宫胎盘和血管组织中的β-内酰胺酶表达的增加以及胎儿生长受限的假设。